Bis-quaternary ammonium salts of amsonic acid



ElS-QUATERNARY AMWGNHUM ALT 49F AIVEGNHJ ACE) Ronald Slack, Chelsea,London, England, assignor to 1 day 63 Baker Limited, Dagenham, England,a corporation of Great Britain No Drawing. Application February 4, 1954Serial No. $33,290

Claims priority, application Great Eritain February 17, 1%53 6 Claims.(Ci. 26il-313) wherein R and R each rep-resent the same or a dift'erentlower alkyl group, R R R and R are the same or are different and eitherthey represent individual lower alkyl groups or the pairs R R and R Rrespectively form with the adjacent nitrogen atom a saturatedheterocyclic group such as a pyrrolidino or morpholino group, irepresents a trimethylene or phenylene group or a divalent cyclohexaneresidue and Z represents an alkylene chain containing from 1 to 8 carbonatoms.

Bis-quaternary salts containing a cation of the aforesaid type are ofconsiderable interest, many of them having already been shown to possessuseful therapeutic properties (see the specifications of copendingapplication Seria No. 259,317, now Patent No. 2,667,493; applicatienSerial No. 326,602, now abandoned; and application Serial No. 338,618,now Patent No. 2,731,500 and Patent No. 2,661,370). However, many ofsuch salts are readily soiuble in water and their manufacture in thepure state with good yield is complicated by the difficultiesexpericnced in the removal of soluble lay-products.

It is the object of the present invention to provide new intermediatesfrom which the above bis-quaternary ammonium salts can readily beprepared in good yield on a commercial scale. These new intermediatesare salts of the foregoing type containing the anion derived from 44-diamino-stilbene-2 2-disulphonic acid (hereinafter called amsonic acidwhile its salts are hereinafter called amsonates) and may be representedas follows:

where the various variables have respectively the significancehereinbefore designated and A represents the residue of amsonic acid.

According to the present invention these new amsonates are obtainedthrough the double-decomposition in aqueous solution of a water-solublebis-quaternary ammonium salt of the aforesaid type by adding to thatsolution a water-soluble amsonate.

The new amsonates are very sparingly soluble in water at normaltemperatures although they will form solutions of reasonableconcentration at elevated temperatures. It is, therefore, a simplematter to isolate the new amsonates from aqueous solutions in which theyare prepared. Since amsonic acid itself is substantially insoluble inwater even at boiling point, the new amsonates 2,827,466 Patented Mar.18, 1958 ice provide a convenient and simple route to the more solublecorresponding bis-quaternary salts uncontaminated by the solubleby-products. Thus amsonic acid is precipitated by the addition of anacid to a solution or suspension of a quaternary ammonium amsonateleaving the quaternary ammonium salt corresponding to the added acid insolution in a substantially pure state. It may be isolated from thesolution by methods known per se (i. e. described in the literature).

It will be appreciated that the process of the present invention can beregarded as a step in the production of bis-quaternary ammonium salts ofthe aforesaid types containing an anion of an acid other than amsonicacid and which are more soluble in water than the correspondingamsonate. Thus, in general, the new amsonates will be directly isolated(by precipitation) from aqueous solutions containing one of such salts(for example sulphate, nitrate, halide, sulphonate or methosulphate) bythe addition thereto of a water soluble amsonate such as sodium orammonium amsonate. The precipitated amsonate may then be purified, forexample by recrystallisation from water, and converted into the desiredfinal product by treatment with an acid containing the required anion.

The process of this invention is not only applicable to the productionof known quaternary ammonium salts of the aforesaid general types as ameans for eliminating otherwise necessary purification steps, but alsorenders possible the commercial production of hitherto unknownquaternary ammonium salts of the aforesaid general types that would bedifficult to produce by the application of known methods. Examples ofsalts which can be conveniently prepared using the process of thepresent invention are the bita-rtrates, bisulphate, dihydrogenphosphates, adipates (neutral and acid), benzoates, chlorides, citrates,acid maleates, methosulphates, succinates (neutral and acid) and neutralsulphates.

The process of the present invention is illustrated by the followingexamples.

Example I Hexamethylene 1 6-bis (trimethylammonium bromide) (3.62 g.)was dissolved in water (15 cc.) and added to a solution of pure disodiumamsonate (4.14 g.) in water (10 cc.) at 50 C. crystallisation of paleyellow hexamethonium amsonate began rapidly on cooling and was allowedto proceed at 2 C. for 12-14 hours. The crystalline material (5.34 g.)was filtered 01f, washed with iced water and recrystallised from waterto give pure hexamethonium amsonate (4.7 g.), M. P. (decomp) 280 C.which may, at this stage, contain water of crystallisation. A .sampledried in vacuum at C. over phosphorus pentoxide gave the anhydrous salt,M. P. (decomp.) 293-294" C. The solubility of the salt in water at 12 C.is approximately 0.4%.

The anhydrous amsonate (5.7 g.) prepared as described above, wasdissolved in warm water cc.) and the solution, at 35-40 (3., was treatedwith d-tartaric acid {3.0 g.) in water (10 cc.). The mixture was cooledand the precipitate of amsonic acid was filtered oif and washed wellwith cold water. The combined filtrates were evaporated to dryness.Treatment of the resulting syrup with cold alcohol gave crudehexamethonium bitartrate which was collected and dissolved in boilingmethanol. The solution was again filtered from a little insolublematerial and cooled to give colourless needles of the pure bitartrate,M. P. -1 82 C.

Phenyl-n-propane p-w-bis trimethylammonium) -amsonate was similarlyprepared from the corresponding diiodide as a pale yellow crystallinesolid.

Example 11 Amsonic acid (0.37 g.) was dissolved in aqueous decinormalsodium hydroxide solution (20 cc.) and hexa- \3methylene-1:6-bis-1'-(1'-rnethylpyrrolidinium) di-iodide (0.25 g.) inwater (2.0 cc.) was added. Colourless plates of the sparingly solubleamsonate separated rapidly. After cooling the mixture for some hours,the substance was filtered off, washed and recrystallised from water togive the pure amsonate, M. P. (decomp.) 285-290 C. The solubility of thesalt in Water at C. is approximately 0.13%.

Example III A warm solution of the u-form of cyclohexylethane4-w-bis(trimethylammonium iodide) (8.4 g.), melting at 302304 C.(decomp.) (preparedas described'in copending application Serial No.338,618) in water (20 cc.) was added to a warm, filtered solution-ofamsonic acid;(8.'1.g.) in a mixture of water (60 cc.) and aqueousammonia (8 cc.; sp. gr. 0.880). The crystalline material whichimmediately separated was filtered oil, washedgwith water, and dried invacuo over silicagel. The crude amsonate (10 g.) was recrystallised fromwater 150 'cc.) from which it separated as pale yellow needles, Dryingin vacuo over silica gel, followed by exposure of the solid to theatmosphere gave a hydrate (9.6 g.) which is stable'to atmosphericmoisture.

This product was treated in aqueous suspension with dilute hydrochloricacid, the precipitated amsonic acid filterediolf and the correspondingdi-chloride obtained by concentration of the filtrate in the form of itstrihydrate.

Example IV Example V 5-pedimethylaminophenyl-n amyldimethylamine (4 g.)

was heated under reflux for 48 hours with a solution of ethyl iodidecc.) in ethanol (25 cc.). Removal of the ethanol and excess ethyl iodideby heating on the steam bath (finally in vacuo) gave phenyl-n-pentanep-wbis(dimethylethylammonium. iodide) as an intractable, brown,hygroscopic gums This was dissolved in cold water (10-co), shaken withcharcoal and filtered. The colourless, bright solution was warmed andadded to a warm filtered solution of amsonic'acid (8' g.) in a mix tureof water cc.) and aqueous ammonia (6 cc.; sp. gr. 0.880). After beingkept overnight at 0 C. the bullcoloured, felted, glistening plateletswhich had separated were filtered off, washed with water and dried invacuo over silica gel, The crude amsonate (5.4g) was crystallised fromwater (150 cc.) and the light tan crystalline material thus obtained wasdried as described in Example The last-mentioned product was treated inaqueous suspension with tartaric acid and, after the precipitatedamsonic acid had been removed by filtration, the correspondingbitartrate was obtained by concentration of the filtrate.

Phenyl-n-pentane p-w-bis(methyldiethylammonium iodide) was similarlyconverted into the corresponding amsonatefrom which was prepared thebitartrate by treatment with tartaric acid. 1

Example VI A warm solution of crude pentamethylene-l:5-bis(1methyl-pyrrolidinium bromide) (4 g.) (a colourless, deliquescent,crystalline solid prepared by refluxing lmethylpyrrolidine withl'z5-pentamethylene dibromide in to separate immediately. After beingkept at 0 C. for 3 hours, the crude amsonate was filtered ofi, washedwith water and air-dried at the laboratory temperature overnight to givea hydrated product (4.6 g.).

Example VII tion of 1:4 dibromobutane (648 g.) (B. P. 8990 C./20

mm.; obtained by the action of hydrobromic acid on tetrahydrofuran) inmethanol (2.11 litres). After being heated for a further 18 hours, themethanol and excess diethylrnethylamine were removed by distillation.The residue was diluted with water to give 4 litres of clear, almostcolourless, solution of pH 6.0.

Amsonic acid (1.11 kg.) was suspended in water (4 litres), ammoniasolution (450 cc.; sp. gr. 0.880) was added, and the suspension washeated to 60 C. and stirred until solution was complete. After beingfiltered the ammonium amsonate solution (at 60 C.) was added to thebis-quaternary bromide solution (at 60 C.) and the whole was allowed tostand overnight.

The crystalline precipitate was filtered oil, washed twice with water (1litre) and dried at 35 C. Tetramethylene-1:4-bis(diethylmethylammonium)amsonate (1.478 kg.) was obtained as apale, reddish-brown, sandy powder containing 5% of water. 7

The above product (1.386 kg.) was suspended in water (17 litres).Tartaric acid (0.66 kg), dissolved in water (5 litres), was added to theamsonate suspension during 5 minutes and the mixture was stirred for 2hours at room temperature. The precipitated amsonic acid was filteredoff, washed with distilled water (2 litres) and dried at C.

The filtrate and washings were stirred with charcoal (50 g.) and HyfloSupercel (200 g.) and refiltered. The volume of the colourless filtratewas reduced in vacuo to 2 litres and the resulting concentrated solutionwas stirred with charcoal (5 g.) and Hyflo Supercel (10 g.) and againfiltered. The final filtrate was added during 30 minutes to a stirredmixture of acetone (4 litres) and ethanol (4 litres). Stirring wascontinued for 30 minutes at room temperature and the white crystallineproduct was filtered, washed with acetone (1 litre) and dried at 35 C.Tetramethylene 1:4 bis (diethylmethylammonium hydrogen tartrate)dihydrate (1.129 kg.) was obtained as a colourless crystalline solid, M.P. 201- 205 C.'(with decomposition).

7 I claim: r

1. A compound of the general formula:

wherein R, and R each represents a lower alkyl group,

R R3, R and R when individual groups represent lower alkyl groups andwhen paired as R R and R R respectiyely form with the adjacent nitrogenatom a monocyclic and Z represents an' alkylene chain containing from 1to Scarbon atoms,

5 2. Hexamethyiene-1:6-bis(trimethylammonium)-4:4'- fii y Y PYdiamino-stilbene-I!:2'-disulphonate having the formula:4I4'-d1am1l10-$ti1be116 dlsulphonate having the NH formula:

(am-H, SOr-N-CH: 5 1 (n11 (3H2 |\GH: CH SOr-N-CHI ("3H (CH2)! CH H (CH9;

S03N CHa OH CH5 SO -N-CH; 3. Cyclohexylethane4:w-bisflrimethylammohium)- NEE 4:4 diamino stilbene-2z2' disuiphonatehaving the 15 CHz-CH2 formula: 6. Tetrarnethylene1:4-bis(diethylmethylammonium)- NH: 4:4 diamino-stilbene 2:2disulphonate having the formula: -S O-NC Hz 2 NH, 0 CQHE C I; S O3NCaH Ci1 J3 CH CH3 on c n {E (H I CH3 6 H S0r-N C2 s (PJU; i C2115 ("H3 0 HReferences Cami 1n the file of this patent Q UNITED STATES PATENTS 11m,2,627,491 Szabo et a1 Feb. 3, 1953 4. Phenylethanep:w-bis(trimethy1ammonium) -4:4'- 641,610 Barber June 1953diamino-stilbene-Z:2'-su1phonate having the formula: 2,661,370 Barber1953 NH 2,667,493 Slack et a1. Jan. 26, 1954 /CH3 FOREIGN PATENTSsch-N433 467,745 Canada Aug. 29, 1950

1. A COMPOUND OF THE GENERAL FORMULA:
 5. PENTAMETHYLENE -1:5-BIS(1''-METHYLPYRROLIDINIUM)4:4''-DIAMINO-STILBENE - 2:2'' -DISULPHONATE HAVING THE FORMULA: